The Ku complex: recent advances and emerging roles outside of non-homologous end-joining

Abbasi, Sanna; Parmar, Gursimran; Kelly, Rachel D.; Balasuriya, Nileeka; Schild-Poulter, Caroline

doi:10.1007/s00018-021-03801-1

Cited by 28 publications

(32 citation statements)

References 305 publications

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“…Heterodimerization leads to a positively charged DNA-binding ring that fits sterically around the minor and major DNA grooves. Ku threads inwards on DNA like a nut threaded onto a bolt, with Ku70 positioned close and Ku80 far away to the DNA end ( Yoo et al., 1999 ; Doherty and Jackson, 2001 ; Abbasi et al., 2021 ). Ku binds to dsDNA ends, 5′ and 3′ overhangs, or blunt ends with a higher binding affinity (Kd = 10 –9 M).…”

Section: Structure and Diverse Functions Of Ku70 And Ku80mentioning

confidence: 99%

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The Role of Ku70 as a Cytosolic DNA Sensor in Innate Immunity and Beyond

Sui

Hao

Chang

et al. 2021

Front. Cell. Infect. Microbiol.

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Human Ku70 is a well-known endogenous nuclear protein involved in the non-homologous end joining pathway to repair double-stranded breaks in DNA. However, Ku70 has been studied in multiple contexts and grown into a multifunctional protein. In addition to the extensive functional study of Ku70 in DNA repair process, many studies have emphasized the role of Ku70 in various other cellular processes, including apoptosis, aging, and HIV replication. In this review, we focus on discussing the role of Ku70 in inducing interferons and proinflammatory cytokines as a cytosolic DNA sensor. We explored the unique structure of Ku70 binding with DNA; illustrated, with evidence, how Ku70, as a nuclear protein, responds to extracellular DNA stimulation; and summarized the mechanisms of the Ku70-involved innate immune response pathway. Finally, we discussed several new strategies to modulate Ku70-mediated innate immune response and highlighted some potential physiological insights based on the role of Ku70 in innate immunity.

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Section: Structure and Diverse Functions Of Ku70 And Ku80mentioning

confidence: 99%

“…This illustration was created by using BioRender. The figure was adapted from the 2021 review by Abbasi et al ( Abbasi et al., 2021 ).…”

Section: Introductionmentioning

confidence: 99%

The Role of Ku70 as a Cytosolic DNA Sensor in Innate Immunity and Beyond

Sui

Hao

Chang

et al. 2021

Front. Cell. Infect. Microbiol.

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“…Apart from their indispensable role in DSB repair, the Ku proteins are also involved in other cellular processes, such as transcription, DNA damage response, DNA replication, and telomere maintenance, to name just a few [ 11 , 16 ]. At the chromosomal termini, they form complexes with other telomere-associated proteins protecting the DNA ends from being recognized and processed as DSBs [ 17 ] and preventing inappropriate recombination events involving telomeric repeats [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Ku80 is involved in telomere maintenance but dispensable for genomic stability in Leishmania mexicana

et al. 2021

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Background Telomeres are indispensable for genome stability maintenance. They are maintained by the telomere-associated protein complex, which include Ku proteins and a telomerase among others. Here, we investigated a role of Ku80 in Leishmania mexicana. Leishmania is a genus of parasitic protists of the family Trypanosomatidae causing a vector-born disease called leishmaniasis. Methodology/Principal findings We used the previously established CRISPR/Cas9 system to mediate ablation of Ku80- and Ku70-encoding genes in L. mexicana. Complete knock-outs of both genes were confirmed by Southern blotting, whole-genome Illumina sequencing, and RT-qPCR. Resulting telomeric phenotypes were subsequently investigated using Southern blotting detection of terminal restriction fragments. The genome integrity in the Ku80- deficient cells was further investigated by whole-genome sequencing. Our work revealed that telomeres in the ΔKu80 L. mexicana are elongated compared to those of the wild type. This is a surprising finding considering that in another model trypanosomatid, Trypanosoma brucei, they are shortened upon ablation of the same gene. A telomere elongation phenotype has been documented in other species and associated with a presence of telomerase-independent alternative telomere lengthening pathway. Our results also showed that Ku80 appears to be not involved in genome stability maintenance in L. mexicana. Conclusion/Significance Ablation of the Ku proteins in L. mexicana triggers telomere elongation, but does not have an adverse impact on genome integrity.

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“…After minor processing of the ends by nucleases or polymerases to expose short complementary sequences (1 to 4 nucleotides [nt]), the ligatable termini are then rejoined by Ligase IV, usually within 30 min after DSB. NHEJ typically attempts to repair DSBs first, often resulting in small deletions or insertions and is much faster than HR (7 h or longer is required for HR) ( 4 – 8 ).…”

Section: Introductionmentioning

confidence: 99%

“…For example, it has been recently reported that Ku70/80 heterodimer suppresses MMEJ in Ligase IV-deficient progenitor B cells, deletion of Ku70 in this B cell line significantly increases MMEJ ( 33 ). In addition, Ku has also been shown to be involved in other cellular processes such as telomere maintenance, DNA replication, transcription, and translation control ( 7 , 8 , 37 – 45 ). In this study, to investigate whether Leishmania Ku70 and Ku80 proteins actively participate in DSB repair in the absence of key NHEJ factors Ligase IV and XRCC4, we generated Leishmania donovani Ku70 null mutants and Ku70/80 double gene null mutants.…”

Section: Introductionmentioning

confidence: 99%